JPWO2020252442A5 - - Google Patents

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JPWO2020252442A5
JPWO2020252442A5 JP2021571936A JP2021571936A JPWO2020252442A5 JP WO2020252442 A5 JPWO2020252442 A5 JP WO2020252442A5 JP 2021571936 A JP2021571936 A JP 2021571936A JP 2021571936 A JP2021571936 A JP 2021571936A JP WO2020252442 A5 JPWO2020252442 A5 JP WO2020252442A5
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Priority claimed from PCT/US2020/037706 external-priority patent/WO2020252442A1/en
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灌流バイオリアクター中の灌流量の自動化された測定及び調節を適用する抗体製品の生産のための上流製造プロセスであって、
（ｉ）前記灌流バイオリアクター中に少なくとも１つの哺乳動物細胞培養物を含む液体細胞培養培地を供給する工程であって、前記哺乳動物細胞培養物が、前記抗体製品を発現することができ、及び前記細胞が、前記灌流バイオリアクター中における播種時に少なくとも１×１０＾５細胞／ｍＬの濃度（生細胞密度、ＶＣＤ）を有する工程、
（ｉｉ）前記バイオリアクター中の培地レベルを測定し及び調節するための第１の制御ループであって、設定値を基準にして前記バイオリアクター中の前記培地レベルを測定するレベルプローブ、浸透液量（時間当たりの体積）を測定するために較正された浸透液ポンプ、並びに前記レベルプローブ及び浸透液プローブからの入力に応じて培地ポンプ（供給ポンプ）に応えて、前記バイオリアクターへの前記培地供給量を補正できる前記レベルプローブ及び前記浸透液ポンプからの入力を受け取るレベル制御手段、又は前記レベルプローブ及び前記培地プローブからの入力に応じて前記浸透液ポンプに応えて、前記バイオリアクターからの流出量を補正できる前記レベルプローブ及び前記培地ポンプからの入力を受け取るレベル制御手段を含み、前記バイオリアクター中の前記培地レベルの測定は、予め設定された固定的な時間間隔で行われ、工程（ｉｉ）において、前記予め設定された固定的な時間間隔は、最大１分に対応する、第１の制御ループを提供する工程；
（ｉｉｉ）前記バイオリアクター中の生物量を測定し及び調節するための第２の制御ループであって、前記生物量を測定する前記バイオリアクター中の誘電率プローブ、並びに入力に応じて放出ポンプに応えて、前記バイオリアクターからの放出量を補正できる生物量誘電率プローブからの入力を受け取る生物量制御手段を含み、前記バイオリアクター中の前記生物量の測定は、予め設定された固定的な時間間隔で行われる、第２の制御ループを提供する工程；
（ｉｖ）統合された第１及び第２の制御ループを、前記生物量制御手段及び前記レベル制御手段を統合ユニットに接続することによって提供する工程であって、前記統合ユニットが、自動化された灌流量計算を実施することができ、前記灌流量が、前記生物量値の関数であり、式
灌流量（ｍＬ／分）＝生物量値の関数（誘電率、ＰＣＶ、ＶＣＤ、分光測定値）
及び／又は
灌流量［ｍＬ／分］＝誘電率に基づく灌流量（定数）［ｃｍ／ｐＦ／ｄ］×誘電率値［ｐＦ／ｃｍ］
（式中、前記定数は、前記灌流量［１／ｄ］を前記誘電率［ｐＦ／ｃｍ］で割ったものであり、及び前記誘電率値は、前記バイオリアクター中の生物量がおよその既定の生物量設定値まで増加する第１の期間（増殖期）において０．５～１２０ｐＦ／ｃｍ及び／又は既定の生物量設定値に達した後の生物量安定化の第２の期間（生産期）において２５～１００ｐＦ／ｃｍである）に基づき、前記生物量設定値は、少なくとも３０×１０＾細胞／ｍＬのＶＣＤと等しく、適用される前記灌流量は、増殖期において０．０１～０．１ｎＬ／細胞／ｄの細胞比灌流量（ＣＳＰＲ）に相当し、適用される前記灌流量は、生産期において０．０１～０．４９ｎＬ／細胞／ｄのＣＳＰＲに相当する工程、並びに
（ｖ）前記統合ユニットによって前記灌流量を自動的に補正するか又は維持する工程であって、統合ユニットが、予め設定された固定的な時間間隔で測定された生物量に応じて、前記浸透液ポンプ及び／又は前記培地ポンプに信号を送信して、それぞれ前記ポンプ量を増加させるか又は減少させる工程
を含むプロセス。 An upstream manufacturing process for the production of an antibody product applying automated measurement and regulation of perfusion rate in a perfusion bioreactor, comprising:
(i) providing a liquid cell culture medium comprising at least one mammalian cell culture into said perfusion bioreactor, said mammalian cell culture capable of expressing said antibody product; and said cells having a concentration (viable cell density, VCD) of at least 1 x 10^5 cells/mL at seeding in said perfusion bioreactor;
(ii) a first control loop for measuring and regulating medium level in said bioreactor, comprising a level probe, permeate volume, which measures said medium level in said bioreactor relative to a set point; The media feed to the bioreactor in response to an osmotic fluid pump calibrated to measure (volume per time) and a media pump (feed pump) in response to inputs from the level probe and the osmotic fluid probe. level control means for receiving inputs from said level probe and said permeate pump capable of compensating for volume or output from said bioreactor in response to said permeate pump in response to inputs from said level probe and said medium probe; and level control means for receiving input from said level probe and said medium pump, wherein measurements of said medium level in said bioreactor are made at fixed preset time intervals , step (ii) in providing a first control loop, wherein said preset fixed time interval corresponds to a maximum of 1 minute ;
(iii) a second control loop for measuring and regulating biomass in said bioreactor, comprising a dielectric probe in said bioreactor that measures said biomass, and a bleed pump in response to an input; In response, biomass control means for receiving input from a biomass permittivity probe capable of correcting emissions from said bioreactor, wherein said biomass measurement in said bioreactor is controlled at a preset fixed rate. providing a second control loop that occurs at timed intervals;
(iv) providing integrated first and second control loops by connecting said biomass control means and said level control means to an integrated unit, said integrated unit comprising an automated irrigation system; A flow rate calculation can be performed, wherein the perfusion rate is a function of the biomass value and the formula
Perfusion rate (mL/min) = function of biomass value (permittivity, PCV, VCD, spectrometry)
and/or perfusion rate [mL/min] = perfusion rate based on dielectric constant (constant) [cm/pF/d] x dielectric constant value [pF/cm]
(where the constant is the perfusion rate [1/d] divided by the dielectric constant [pF/cm], and the dielectric constant value is the approximate given amount of biomass in the bioreactor). 0.5-120 pF/cm in a first period (growth phase) of increasing to a biomass setpoint of 0.5-120 pF/cm and/or a second period of biomass stabilization after reaching a predetermined biomass setpoint (production phase ) is 25-100 pF/cm in ), the biomass set point is equal to a VCD of at least 30×10̂ cells/mL, and the applied perfusion rate is between 0.01 and corresponding to a cell specific perfusion rate (CSPR) of 0.1 nL/cell/d, said applied perfusion rate corresponding to a CSPR of 0.01 to 0.49 nL/cell/d in the production phase, and (v) automatically correcting or maintaining the perfusion rate by the integration unit, wherein the integration unit determines the osmotic A process comprising sending a signal to a fluid pump and/or said media pump to increase or decrease said pump volume, respectively. 前記上流製造プロセスが、非連続灌流プロセス、又は連続灌流プロセスである、請求項１に記載のプロセス。 2. The process of claim 1, wherein the upstream manufacturing process is a discontinuous perfusion process or a continuous perfusion process. 工程（ｉ）において、前記細胞が、前記バイオリアクター中での播種時に少なくとも７×１０＾５細胞／ｍＬの濃度を有する、請求項１に記載のプロセス。 2. The process of claim 1, wherein in step (i) the cells have a concentration of at least 7 x 10^5 cells/mL upon seeding in the bioreactor. 工程（ｉｖ）において、前記生物量設定値が、前記製造プロセスが非連続プロセスである場合、３０×１０＾６細胞／ｍＬのＶＣＤに等しく、前記製造プロセスが連続製造プロセスである場合、６５×１０＾６細胞／ｍＬのＶＣＤに等しい、請求項１に記載のプロセス。 In step (iv), the biomass set point is equal to a VCD of 3 0×10̂6 cells/mL if the manufacturing process is a discontinuous process and 65 if the manufacturing process is a continuous manufacturing process 2. The process of claim 1, equal to VCD of x 10^6 cells/mL. 工程（ｉｖ）において、前記細胞培養物の増殖が、少なくとも４日間、又は少なくとも７日間、又は少なくとも１２日間若しくは１４日間起こる、請求項１に記載のプロセス。 2. The process of claim 1, wherein in step (iv) the growth of the cell culture occurs for at least 4 days, or for at least 7 days, or for at least 12 days or 14 days. 工程（ｉｉ）において、前記予め設定された固定的な時間間隔が、最大３０秒、又は最大１０、９、８、７、６、５、４、３、２、１、若しくは０．５秒に相当する、請求項１に記載のプロセス。 In step (ii), the preset fixed time interval is up to 30 seconds, or up to 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0.5 seconds 2. The process of claim 1, corresponding to 工程（ｉｉｉ）において、前記予め設定された固定的な時間間隔が、最大１分又は３０秒、又は最大１０、９、８、７、６、５、４、３、２、１、若しくは０．５秒に相当する、請求項１に記載のプロセス。 In step (iii), said preset fixed time interval is up to 1 minute or 30 seconds, or up to 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0. 2. The process of claim 1, corresponding to 5 seconds. 工程（ｖ）において、前記予め設定された固定的な時間間隔が、最大１分又は３０秒、又は最大１０、９、８、７、６、５、４、３、２、１、若しくは０．５秒に相当する、請求項１に記載のプロセス。 In step (v), said preset fixed time interval is up to 1 minute or 30 seconds, or up to 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0. 2. The process of claim 1, corresponding to 5 seconds. 増殖期における前記誘電率が前記製造プロセスが連続製造プロセスである場合、０．７０～１２０ｐＦ／ｃｍ、又は０．７３～７０．７ｐＦ／ｃｍ、又は１～２０ｐＦ／ｃｍ若しくは１００～１１７ｐＦ／ｃｍである、請求項１に記載のプロセス。 The dielectric constant in the growth phase is 0.70 to 120 pF/cm, or 0.70 to 120 pF/cm when the manufacturing process is a continuous manufacturing process. 73-70.7 pF/cm, or 1-20 pF/cm or 100-117 pF/cm. 連続製造における前記誘電率に基づく細胞比灌流量が、増殖期において０．０１～０．０４９ｃｍ／ｐＦ／ｄ、又は０．０１５～０．０４ｃｍ／ｐＦ／ｄ、又は０．０２～０．０４ｃｍ／ｐＦ／ｄ、又は０．０２６６～０．０４ｃｍ／ｐＦ／ｄである、請求項１に記載のプロセス。 The cell specific perfusion rate based on the dielectric constant in continuous production is 0.01 to 0.049 cm/pF/d, or 0.015 to 0.04 cm/pF/d, or 0.02 to 0.04 cm/pF/d in the growth phase. 04 cm/pF/d , or 0.0266 to 0.04 cm/pF/d. 適用される前記灌流量が、増殖期において０．０２～０．０８ｎＬ／細胞／ｄ、又は増殖期において０．０２７～０．０７６ｎＬ／細胞／ｄのＣＳＰＲに相当する、請求項１に記載のプロセス。 The perfusion rate applied is 0.00 in the growth phase. 02-0.08 nL/cell/d, or a CSPR of 0.027-0.076 nL/cell/d in the growth phase. 生産期における前記誘電率が、５５～８５ｐＦ／ｃｍ、又は６０～７５ｐＦ／ｃｍ、又は６２～７３ｐＦ／ｃｍである、請求項１に記載のプロセス。 The process of claim 1, wherein the dielectric constant in production is 55-85 pF/cm, or 60-75 pF/cm, or 62-73 pF/cm. 前記誘電率に基づく細胞比灌流量が、生産期において０．０１～０．０４ｃｍ／ｐＦ／ｄ、又は０．０１～０．０３５ｃｍ／ｐＦ／ｄ、又は０．０１～０．０２６６ｃｍ／ｐＦ／ｄである、請求項１に記載のプロセス。 The cell specific perfusion rate based on the dielectric constant is 0.01 to 0.04 cm/pF/d, or 0.01 to 0.035 cm/pF/d, or 0.01 to 0.0266 cm/pF/d in the production phase. 2. The process of claim 1, wherein d. 適用される前記灌流量が、生産期において０．０１５～０．０４ｎＬ／細胞／ｄ、又は０．０２３～０．０３５ｎＬ／細胞／ｄのＣＳＰＲに相当する、請求項１に記載のプロセス。 If the perfusion rate applied is 0.00 in the production phase. The process of claim 1, which corresponds to a CSPR of 0.015-0.04 nL/cell/d, or 0.023-0.035 nL/cell/d. 前記生産期が、少なくとも１４日、又は少なくとも２１、２２、２３、２４、２５、２６、２７、２８、２９、３０、３１、若しくは３２日であり、ここで前記生産プロセスが連続製造プロセスであるか、又は
少なくとも３日、又は４日若しくは５日であり、ここで前記生産プロセスが非連続製造プロセスである、請求項１に記載のプロセス。 said production period is at least 14 days, or at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , or 32 days, and wherein said production process is a continuous manufacturing process or at least 3 days, or 4 days or 5 days, wherein the production process is a discontinuous manufacturing process. 前記抗体製品が、モノクローナル抗体などの全長抗体、又は非全長分子である、請求項１に記載のプロセス。 2. The process of claim 1, wherein said antibody product is a full-length antibody, such as a monoclonal antibody, or a non-full-length molecule. 前記抗体製品が、二重特異性である、すなわち、標的及び／又はエフェクター細胞にそれぞれ結合する全長抗体又はそのフラグメントに基づく全長抗体又は分子である、請求項１６に記載のプロセス。 17. A process according to claim 16, wherein said antibody product is bispecific , ie a full length antibody or molecule based on a full length antibody or a fragment thereof that binds to target and/or effector cells respectively. 前記二重特異性抗体製品が、融合タンパク質である、請求項１７に記載のプロセス。 18. The process of claim 17, wherein said bispecific antibody product is a fusion protein. 前記抗体製品が、標的及びエフェクター分子にそれぞれ結合する第１の結合ドメイン及び第２の結合ドメインを含む二重特異性非全長分子である、請求項１７に記載のプロセス。 18. The process of claim 17, wherein said antibody product is a bispecific non-full-length molecule comprising a first binding domain and a second binding domain that bind target and effector molecules, respectively. 前記二重特異性分子が、二重特異性Ｔ細胞エンゲージャー分子である、請求項１７に記載のプロセス。 18. The process of claim 17, wherein said bispecific molecule is a bispecific T cell engager molecule. 前記二重特異性分子が、ヒト血清アルブミン（ＨＡＳ）、ＨＡＳ結合ドメイン、ヘテロＦｃドメイン又はＩｇＧ抗体に由来するＦｃに基づく半減期延長部分から選択される半減期延長部分、又はｓｃＦｃ半減期延長部分を含む、請求項２０に記載のプロセス。 wherein said bispecific molecule is a half-life extending moiety selected from human serum albumin (HAS), a HAS binding domain, a hetero-Fc domain or an Fc-based half-life extending moiety derived from an IgG antibody, or scFc half-life extending 21. The process of Claim 20, comprising a portion. 前記二重特異性抗体コンストラクトの前記第１の結合ドメインが、ＣＤ１９、ＣＤ３３、ＥＧＦＲｖＩＩＩ、ＭＳＬＮ、ＣＤＨ１９、ＦＬＴ３、ＤＬＬ３、ＣＤＨ３、ＥｐＣＡＭ、ＣＤ７０、ＭＵＣ１７、ＣＬＤＮ１８、ＢＣＭＡ及びＰＳＭＡからなる群から選択される少なくとも１つの標的細胞の表面抗原に結合する、請求項１９に記載のプロセス。 said first binding domain of said bispecific antibody construct is selected from the group consisting of CD19, CD33, EGFRvIII, MSLN, CDH19, FLT3, DLL3, CDH3, EpCAM, CD70, MUC17, CLDN18, BCMA and PSMA 20. The process of claim 19, which binds to at least one target cell surface antigen. 前記二重特異性抗体製品の前記第２の結合ドメインが、ＣＤ３に結合する、請求項１９に記載のプロセス。 20. The process of claim 19, wherein said second binding domain of said bispecific antibody product binds CD3. 前記第１の結合ドメインが、
（ａ）配列番号１に示されるとおりのＣＤＲ－Ｈ１、配列番号２に示されるとおりのＣＤＲ－Ｈ２、配列番号３に示されるとおりのＣＤＲ－Ｈ３、配列番号４に示されるとおりのＣＤＲ－Ｌ１、配列番号５に示されるとおりのＣＤＲ－Ｌ２及び配列番号６に示されるとおりのＣＤＲ－Ｌ３、
（ｂ）配列番号２９に示されるとおりのＣＤＲ－Ｈ１、配列番号３０に示されるとおりのＣＤＲ－Ｈ２、配列番号３１に示されるとおりのＣＤＲ－Ｈ３、配列番号３４に示されるとおりのＣＤＲ－Ｌ１、配列番号３５に示されるとおりのＣＤＲ－Ｌ２及び配列番号３６に示されるとおりのＣＤＲ－Ｌ３、
（ｃ）配列番号４２に示されるとおりのＣＤＲ－Ｈ１、配列番号４３に示されるとおりのＣＤＲ－Ｈ２、配列番号４４に示されるとおりのＣＤＲ－Ｈ３、配列番号４５に示されるとおりのＣＤＲ－Ｌ１、配列番号４６に示されるとおりのＣＤＲ－Ｌ２及び配列番号４７に示されるとおりのＣＤＲ－Ｌ３、
（ｄ）配列番号５３に示されるとおりのＣＤＲ－Ｈ１、配列番号５４に示されるとおりのＣＤＲ－Ｈ２、配列番号５５に示されるとおりのＣＤＲ－Ｈ３、配列番号５６に示されるとおりのＣＤＲ－Ｌ１、配列番号５７に示されるとおりのＣＤＲ－Ｌ２及び配列番号５８に示されるとおりのＣＤＲ－Ｌ３、
（ｅ）配列番号６５に示されるとおりのＣＤＲ－Ｈ１、配列番号６６に示されるとおりのＣＤＲ－Ｈ２、配列番号６７に示されるとおりのＣＤＲ－Ｈ３、配列番号６８に示されるとおりのＣＤＲ－Ｌ１、配列番号６９に示されるとおりのＣＤＲ－Ｌ２及び配列番号７０に示されるとおりのＣＤＲ－Ｌ３、
（ｆ）配列番号８３に示されるとおりのＣＤＲ－Ｈ１、配列番号８４に示されるとおりのＣＤＲ－Ｈ２、配列番号８５に示されるとおりのＣＤＲ－Ｈ３、配列番号８６に示されるとおりのＣＤＲ－Ｌ１、配列番号８７に示されるとおりのＣＤＲ－Ｌ２及び配列番号８８に示されるとおりのＣＤＲ－Ｌ３、
（ｇ）配列番号９４に示されるとおりのＣＤＲ－Ｈ１、配列番号９５に示されるとおりのＣＤＲ－Ｈ２、配列番号９６に示されるとおりのＣＤＲ－Ｈ３、配列番号９７に示されるとおりのＣＤＲ－Ｌ１、配列番号９８に示されるとおりのＣＤＲ－Ｌ２及び配列番号９９に示されるとおりのＣＤＲ－Ｌ３、
（ｈ）配列番号１０５に示されるとおりのＣＤＲ－Ｈ１、配列番号１０６に示されるとおりのＣＤＲ－Ｈ２、配列番号１０７に示されるとおりのＣＤＲ－Ｈ３、配列番号１０９に示されるとおりのＣＤＲ－Ｌ１、配列番号１１０に示されるとおりのＣＤＲ－Ｌ２及び配列番号１１１に示されるとおりのＣＤＲ－Ｌ３、
（ｉ）配列番号１１５に示されるとおりのＣＤＲ－Ｈ１、配列番号１１６に示されるとおりのＣＤＲ－Ｈ２、配列番号１１７に示されるとおりのＣＤＲ－Ｈ３、配列番号１１８に示されるとおりのＣＤＲ－Ｌ１、配列番号１１９に示されるとおりのＣＤＲ－Ｌ２及び配列番号１２０に示されるとおりのＣＤＲ－Ｌ３、
（ｊ）配列番号１２６に示されるとおりのＣＤＲ－Ｈ１、配列番号１２７に示されるとおりのＣＤＲ－Ｈ２、配列番号１２８に示されるとおりのＣＤＲ－Ｈ３、配列番号１２９に示されるとおりのＣＤＲ－Ｌ１、配列番号１３０に示されるとおりのＣＤＲ－Ｌ２及び配列番号１３１に示されるとおりのＣＤＲ－Ｌ３、
（ｋ）配列番号１３７に示されるとおりのＣＤＲ－Ｈ１、配列番号１３８に示されるとおりのＣＤＲ－Ｈ２、配列番号１３９に示されるとおりのＣＤＲ－Ｈ３、配列番号１４０に示されるとおりのＣＤＲ－Ｌ１、配列番号１４１に示されるとおりのＣＤＲ－Ｌ２及び配列番号１４２に示されるとおりのＣＤＲ－Ｌ３、
（ｌ）配列番号１５２に示されるとおりのＣＤＲ－Ｈ１、配列番号１５３に示されるとおりのＣＤＲ－Ｈ２、配列番号１５４に示されるとおりのＣＤＲ－Ｈ３、配列番号１５５に示されるとおりのＣＤＲ－Ｌ１、配列番号１５６に示されるとおりのＣＤＲ－Ｌ２及び配列番号１５７に示されるとおりのＣＤＲ－Ｌ３、
（ｍ）配列番号１６７に示されるとおりのＣＤＲ－Ｈ１、配列番号１６８に示されるとおりのＣＤＲ－Ｈ２、配列番号１６９に示されるとおりのＣＤＲ－Ｈ３、配列番号１７０に示されるとおりのＣＤＲ－Ｌ１、配列番号１７１に示されるとおりのＣＤＲ－Ｌ２及び配列番号１７２に示されるとおりのＣＤＲ－Ｌ３、
（ｎ）配列番号２０３に示されるとおりのＣＤＲ－Ｈ１、配列番号２０４に示されるとおりのＣＤＲ－Ｈ２、配列番号２０５に示されるとおりのＣＤＲ－Ｈ３、配列番号２０６に示されるとおりのＣＤＲ－Ｌ１、配列番号２０７に示されるとおりのＣＤＲ－Ｌ２及び配列番号２０８に示されるとおりのＣＤＲ－Ｌ３、
（ｏ）配列番号２１４に示されるとおりのＣＤＲ－Ｈ１、配列番号２１５に示されるとおりのＣＤＲ－Ｈ２、配列番号２１６に示されるとおりのＣＤＲ－Ｈ３、配列番号２１７に示されるとおりのＣＤＲ－Ｌ１、配列番号２１８に示されるとおりのＣＤＲ－Ｌ２及び配列番号２１９に示されるとおりのＣＤＲ－Ｌ３、
（ｐ）配列番号２２６に示されるとおりのＣＤＲ－Ｈ１、配列番号２２７に示されるとおりのＣＤＲ－Ｈ２、配列番号２２８に示されるとおりのＣＤＲ－Ｈ３、配列番号２２９に示されるとおりのＣＤＲ－Ｌ１、配列番号２３０に示されるとおりのＣＤＲ－Ｌ２及び配列番号２３１に示されるとおりのＣＤＲ－Ｌ３；並びに
（ｑ）配列番号２３８に示されるとおりのＣＤＲ－Ｈ１、配列番号２３９に示されるとおりのＣＤＲ－Ｈ２、配列番号２４０に示されるとおりのＣＤＲ－Ｈ３、配列番号２４１に示されるとおりのＣＤＲ－Ｌ１、配列番号２４２に示されるとおりのＣＤＲ－Ｌ２及び配列番号２４３に示されるとおりのＣＤＲ－Ｌ３
からなる群から選択されるＣＤＲ－Ｈ１、ＣＤＲ－Ｈ２及びＣＤＲ－Ｈ３を含むＶＨ領域、並びにＣＤＲ－Ｌ１、ＣＤＲ－Ｌ２及びＣＤＲ－Ｌ３を含むＶＬ領域を含む、請求項１９に記載のプロセス。 wherein the first binding domain is
(a) CDR-H1 as set forth in SEQ ID NO:1, CDR-H2 as set forth in SEQ ID NO:2, CDR-H3 as set forth in SEQ ID NO:3, CDR-L1 as set forth in SEQ ID NO:4 , CDR-L2 as set forth in SEQ ID NO:5 and CDR-L3 as set forth in SEQ ID NO:6,
(b) CDR-H1 as set forth in SEQ ID NO:29, CDR-H2 as set forth in SEQ ID NO:30, CDR-H3 as set forth in SEQ ID NO:31, CDR-L1 as set forth in SEQ ID NO:34 , CDR-L2 as set forth in SEQ ID NO:35 and CDR-L3 as set forth in SEQ ID NO:36,
(c) CDR-H1 as set forth in SEQ ID NO:42, CDR-H2 as set forth in SEQ ID NO:43, CDR-H3 as set forth in SEQ ID NO:44, CDR-L1 as set forth in SEQ ID NO:45 , CDR-L2 as set forth in SEQ ID NO:46 and CDR-L3 as set forth in SEQ ID NO:47,
(d) CDR-H1 as set forth in SEQ ID NO:53, CDR-H2 as set forth in SEQ ID NO:54, CDR-H3 as set forth in SEQ ID NO:55, CDR-L1 as set forth in SEQ ID NO:56 , CDR-L2 as set forth in SEQ ID NO:57 and CDR-L3 as set forth in SEQ ID NO:58,
(e) CDR-H1 as set forth in SEQ ID NO:65, CDR-H2 as set forth in SEQ ID NO:66, CDR-H3 as set forth in SEQ ID NO:67, CDR-L1 as set forth in SEQ ID NO:68 , CDR-L2 as set forth in SEQ ID NO:69 and CDR-L3 as set forth in SEQ ID NO:70,
(f) CDR-H1 as set forth in SEQ ID NO:83, CDR-H2 as set forth in SEQ ID NO:84, CDR-H3 as set forth in SEQ ID NO:85, CDR-L1 as set forth in SEQ ID NO:86 , CDR-L2 as set forth in SEQ ID NO:87 and CDR-L3 as set forth in SEQ ID NO:88,
(g) CDR-H1 as set forth in SEQ ID NO:94, CDR-H2 as set forth in SEQ ID NO:95, CDR-H3 as set forth in SEQ ID NO:96, CDR-L1 as set forth in SEQ ID NO:97 , CDR-L2 as set forth in SEQ ID NO:98 and CDR-L3 as set forth in SEQ ID NO:99,
(h) CDR-H1 as set forth in SEQ ID NO:105, CDR-H2 as set forth in SEQ ID NO:106, CDR-H3 as set forth in SEQ ID NO:107, CDR-L1 as set forth in SEQ ID NO:109 , CDR-L2 as set forth in SEQ ID NO: 110 and CDR-L3 as set forth in SEQ ID NO: 111,
(i) CDR-H1 as set forth in SEQ ID NO:115, CDR-H2 as set forth in SEQ ID NO:116, CDR-H3 as set forth in SEQ ID NO:117, CDR-L1 as set forth in SEQ ID NO:118 , CDR-L2 as set forth in SEQ ID NO: 119 and CDR-L3 as set forth in SEQ ID NO: 120,
(j) CDR-H1 as set forth in SEQ ID NO:126, CDR-H2 as set forth in SEQ ID NO:127, CDR-H3 as set forth in SEQ ID NO:128, CDR-L1 as set forth in SEQ ID NO:129 , CDR-L2 as set forth in SEQ ID NO: 130 and CDR-L3 as set forth in SEQ ID NO: 131,
(k) CDR-H1 as set forth in SEQ ID NO:137, CDR-H2 as set forth in SEQ ID NO:138, CDR-H3 as set forth in SEQ ID NO:139, CDR-L1 as set forth in SEQ ID NO:140 , CDR-L2 as set forth in SEQ ID NO: 141 and CDR-L3 as set forth in SEQ ID NO: 142,
(l) CDR-H1 as set forth in SEQ ID NO:152, CDR-H2 as set forth in SEQ ID NO:153, CDR-H3 as set forth in SEQ ID NO:154, CDR-L1 as set forth in SEQ ID NO:155 , CDR-L2 as set forth in SEQ ID NO: 156 and CDR-L3 as set forth in SEQ ID NO: 157,
(m) CDR-H1 as set forth in SEQ ID NO:167, CDR-H2 as set forth in SEQ ID NO:168, CDR-H3 as set forth in SEQ ID NO:169, CDR-L1 as set forth in SEQ ID NO:170 , CDR-L2 as set forth in SEQ ID NO: 171 and CDR-L3 as set forth in SEQ ID NO: 172,
(n) CDR-H1 as set forth in SEQ ID NO:203, CDR-H2 as set forth in SEQ ID NO:204, CDR-H3 as set forth in SEQ ID NO:205, CDR-L1 as set forth in SEQ ID NO:206 , CDR-L2 as set forth in SEQ ID NO:207 and CDR-L3 as set forth in SEQ ID NO:208,
(o) CDR-H1 as set forth in SEQ ID NO:214, CDR-H2 as set forth in SEQ ID NO:215, CDR-H3 as set forth in SEQ ID NO:216, CDR-L1 as set forth in SEQ ID NO:217 , CDR-L2 as set forth in SEQ ID NO:218 and CDR-L3 as set forth in SEQ ID NO:219,
(p) CDR-H1 as set forth in SEQ ID NO:226, CDR-H2 as set forth in SEQ ID NO:227, CDR-H3 as set forth in SEQ ID NO:228, CDR-L1 as set forth in SEQ ID NO:229 , CDR-L2 as set forth in SEQ ID NO:230 and CDR-L3 as set forth in SEQ ID NO:231; and (q) CDR-H1 as set forth in SEQ ID NO:238, CDR as set forth in SEQ ID NO:239 -H2, CDR-H3 as set forth in SEQ ID NO:240, CDR-L1 as set forth in SEQ ID NO:241, CDR-L2 as set forth in SEQ ID NO:242 and CDR-L3 as set forth in SEQ ID NO:243
20. The process of claim 19, comprising a VH region comprising CDR-H1, CDR-H2 and CDR-H3, and a VL region comprising CDR-L1, CDR-L2 and CDR-L3 selected from the group consisting of: 灌流培養が、少なくとも７日間、又は少なくとも１４、１５、１６、１７、１８、１９、２０、２１、２２、２３、２４、２５、２６、２７若しくは２８日間、又は少なくとも３５日間、規定の細胞比灌流量で供給し、前記バイオリアクターから余分な細胞を抜いて、前記生物量設定値を維持することによって連続的に行われている、請求項１に記載のプロセス。 perfusion culture for at least 7 days, or for at least 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days, or for at least 35 days 2. The process of claim 1, wherein the biomass set point is maintained by feeding at a specific perfusion rate and withdrawing excess cells from the bioreactor.
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